Cell adaptation, injury, and death play important roles in disease pathogenesis according to Rudolph Virchow's theory. Adaptation is a reversible cellular response to stress that allows cells to survive physiological or pathological stimuli. If stress is too severe or prolonged, it can lead to cell injury, which may be reversible or irreversible. The main types of cellular adaptation include hyperplasia, hypertrophy, atrophy, metaplasia, and dystrophy. Cell injury damages intracellular structures and impairs cellular functions. The two main types of cell death are necrosis, which is unregulated, and apoptosis, which is programmed and controlled. Necrosis leads to cell lysis while apoptosis involves fragmentation into apoptotic bodies.
2. Diseases
• Modern pathology is based on the theory of Rudolph Virchow who
states that, all diseases starts with the molecular and functional
changes to the cells.
3.
4. Cell adaptation
Definition:
Adaptation is the reversible structural and functional change of the cell
due to some pathologic stimuli or severe physiologic stress and the cell
can continue to survive and function by achieving new steady state.
The adaptive responses are - change to the number, size, phenotype,
metabolic activity or functions of cell. These changes cause –
- Modulation of functioning of cells
- Increase viability of cells
When the stress is removed, the cell can return to the original steady
state without any harmful consequences
5. Types of Cell Adaptation
1. Physiologic adaptations: Responses of cell to normal stimulation
usually by hormones or other endogenous ligands. Cells must
constantly adapt to changes in their environment, even under normal
conditions.
2. Pathologic adaptations: Responses of cell to abnormal/noxious
stimulation that provide the ability to survive in the changed
environment and perhaps avoid injury
6. Forms of Adaptation
• Adaptation may occur in several distinct forms –
1. Hyperplasia
2. Hepertrophy
3. Atrophy
4. Metaplasia
5. Dystrophy:
6. Dysplasia: Disorderly proliferation of cells where cells have
lost uniformity and architectural orientation in tissue. This is
not cancer.
7. Hyperplasia
Definition:
Hyperplasia is the adaptive process where the number of cells in an organ
or tissue increases resulting in increased volume of the organ or tissue.
Stimuli
Normal
Hyperplasia
Cell
Basolateral
membrane
Hyperplasia may occur together with hypertrophy and may be triggered
by same stimuli. But hyperplasia will only occur in cells which can divide. So the
cells must be able to synthesize DNA and permit mitosis.
8. • Why hyperplasia occurs?
- Increased workload
- Increased physiologic requirements
- For wound healing
• Types:
1. Physiologic hyperplasia
a. Hormonal hyperplasia
b. Compensatory hyperplasia
2. Pathologic hyperplasia
a. Excessive stimulation
b. Failure of regulation
9. Mechanism of hyperplasia
Hyperplasia occurs usually due to combined effects of following –
1. Increased local production of growth factor
2. Increased production of growth factor receptor (GFR) in responding
cell
3. Activation of intracellular pathway of transcription factor synthesis.
• Hyperplasia is mainly caused by growth factor-driven
proliferation or by increased cell production from the tissue stem cells
(unipotent). For example, in liver regeneration, the process is mostly
paracrine signaled growth factor-driven proliferation.
10. Hyperplasia is a controlled process in the sense that when the stimuli are removed the cell returns to
normal state. This is true for even pathologic hyperplasia. On the other hand, in cancer, the growth can’t
be controlled. Hence, hyperplasia is different from cancer but hyperplasia may give support to cancerous
proliferation (patients with endometrial hyperplasia are at risk of endometrial cancer
11. Hypertrophy
• Definition:
It is the adaptive process in which the size of cell is increased in
response to stimuli resulting in increase of the organ/tissue.
12. Why hypertrophy occurs?
Hypertrophy is triggered by
- Mechanical stress/workload (e.g. in cardiac and skeletal
muscle)
- Trophic factors such as increased nutritional supply, vasoactive
agents (endothelin-1, angiotensin II, α-adrenergic agonists) and
growth factors (e.g. Insulin like growth factor, IGF-1; TGF-β
Fibroblast growth factors), .
13. Types of Hypertrophy
Hypertrophy is of two types –
1. Physiologic hypertrophy: This is physiologic growth of cells to
meet increased functional demand. E.g. estrogen induced growth
of uterus during pregnancy, bulging of muscles of bodybuilders
etc.
2. Pathologic hypertrophy: Pathologic condition causes increased
functional demand which result in hypertrophy. E.g. hypertrophy
of heart due to chronic hemodynamic overload. The chronic
hemodynamic overload is due to hypertension or faulty heart
valves. Here, the myofilaments are increased in number, hence
each myocyte is enlarged. So each myocyte can generate more
force resulting in greater work capacity of muscle. If the demand
surpasses the capacity of muscle to enlarge then, cardiac failure
ensues
15. Mechanism of hypertrophy
• hypertrophy is caused by mechanical stress, growth factors and
vasoactive agents. These stimuli work together to
- Increase muscle protein synthesis. Mainly two biochemical processes
are involved – phosphoinositid-3-kinase/Akt pathway (important in
physiologic hypertrophy) and GPCR downstream effect (important in
pathologic pathway).
- Also contractile proteins may be switched between adult and
fetal/neonatal forms. Exemplary, α-myosin heavy chain is switched to
β-myosin heavy chain which gives slower and energetically
economical contraction.
• In addition, some genes which are only expressed in fetal/neonatal
stage, is expressed again. Exemplary, ANF gene is expressed in atrium
and ventricle of embryonic heart but not after birth. During
hypertrophy it is expressed again. ANF (Atrial Natriuretic Factor)
causes decreased blood volume and pressure hence decrease
hemodynamic load
16. Atrophy
• Definition:
It is the adaptive process of cell to a stimulus where are cell
shrink in size by loss of cellular substances.
Atrophy is the reduced size of an organ or tissue due to decrease
in cell size and number.
17. Why atrophy occurs?
• Decreased workload
• Loss of innervation
• Diminished blood supply
• Inadequate nutrition
• Loss of endocrine stimulation
• Pressure: Pressure can cause atrophy
• Aging
18. Types of Atrophy
Atrophy is also of two types –
1. Physiologic atrophy: e.g. decrease in size of uterus after parturition,
atrophy of the notochord and some other embryonic structures during
fetal development. Such atrophy is normal physiologic process and not
due to any disease conditions.
2. Pathologic atrophy: This may be localized or generalized. Example
include, muscle atrophy in marasmus.
19. Mechanism of atrophy
The main reason for atrophy is protein degradation. If the degradation rate
increased and synthesis is decreased atrophy will occur. Followings are possible
protein degradation paths –
1. Lysosomes: It contains proteolytic enzymes. For example acid hydrolase –
cathepsins. These enzymes degrade extracellular protein (when endocytosed) as
well as cytosolic proteins.
2. Ubiquitin-proteasome pathway: This pathway is thought to be responsible for
the accelerated proteolysis seen in a variety of catabolic conditions.
• Hormones e.g. (glucocorticoids and thyroid hormone) and cytokines (TNF)
stimulate this mechanism while insulin opposes it.
3. Autophagic vacuoles: When nutrient shortage occurs, the intracellular organelles
and portion of cytosol are first sequestered in vacuoles which are then bound to
membrane. Eventually the vacuoles are fused with lysosome forming
lysophagosome. Thus the cellular components are digested and used as nutrients
20. Metaplasia
• Definition:
Metaplasia is a reversible change in which one adult cell type is
replaced by another adult cell type.
In this manner, the cells which are more susceptible to the stress
is replaced by cells which are less susceptible in an attempt to
adapt to the stress.
21. Causes of metaplasia
1. Changes in the environment: e.g. stones in excretory ducts of salivary
glands, pancreas or bile duct may cause columner cells being replaced by
stratified squamus cells.
2. Irritation or inflammation: In chronic irritation e.g. habitual cigarette
smokers, the columner epithelial cells respiratory tract are replaced by
stratified squamus epithelial cells.
3. Nutritional: Vitamin A (retinoic acid) deficiency causes squamus
metaplasia in respiratory tract.
22. Mechanism of metaplasia
The adult (differentiated) cells come from stem cells (undifferentiated).
Stimuli responsible for metaplasia cause these stems cells to undergo
differentiation in a new pathway. For example, retinoic acid controls
expression of genes and thus differentiation through nuclear retinoid
receptors. If vitamin A is deficient, then this regulation is lost and cell
divides in another path.
• Consequences of metaplasia:
Most of the time, epithelial metaplasia is detrimental. Cancer can also form
around the area of metaplasia. Thus epithelial metaplasia is a double edged
sword.
23. Cell injury
• Definition:
Cell injury is the state of cell when cell is stressed so severely that
it can’t adapt to the stress.
Such stress can result from extrinsic factors or intrinsic
abnormalities or inherently damaging agents. Injury may
progress through reversible stage and culminate in cell death
24. Types of cell injury
Injury is of two types –
1. Reversible injury: If injurious stimulus is mild and short-lasting
then the cell can return to normal state. Such injury is termed
reversible injury.
2. Irreversible injury: When the injurious stimulus is severe and
also continuous, the cell can’t recover and eventually dies. This
type of injury is termed irreversible injury.
25. Causes of cell injury
• Oxygen deprivation
• Physical agents
• Chemical agents and drugs
• Infectious agents:
• Immunologic reactions
• Genetic derangement
• Nutritional imbalances
27. • Factors affecting cell injury:
1. Type, duration and severity of injury. These determine the cellular
response.
2. Type, state and adaptability of the responding cell.
3. The biochemical pathways affected.
• Common targets affected by injurious stimuli:
1. ATP production
2. Plasma membrane integrity which control ionic and osmotic
homeostasis of cell and its organelles.
3. Cytoskeleton
4. Protein synthesis
5. The integrity of the genetic apparatus of the cell
28. Cell death
• Introduction:
Cell death is the most crucial event in the development of disease. It is
the end result of progressive injury. It results from diverse causes e.g.
- Ischemia
- Infection
- Toxins etc.
• Cell death is a normal and essential process in –
- Embryogenesis
- Development of organs
- Maintenance of homeostasis.
• Two principle path of cellular death are necrosis and apoptosis.
29. Necrosis
• Simply necrosis is the pathologic death of cells
• The mechanism and path of necrosis differs from cell type to
cell type. But the process –
1. Is always pathological
2. Culminates irreversible injury
3. Cell swelling occurs
4. Nuclear change occurs
5. Inflammation is possible
31. Patterns of necrosis
1. Coagulative necrosis: In such case, the architecture of the dead
tissue is preserved in the necrotic area for a long time. This is
probably due to denaturation of the proteolytic enzymes.
2. Liquefactive necrosis: The cellular contents are digested by
enzymes to form a liquid mass.
3. Caseous necrosis: Here the contents of lysed cells are enclosed
in a specific inflammatory border. This is encountered most
commonly in tuberculosis.
32. Apoptosis
• Introduction:
Apoptosis is defined as the programmed death of cells.
• It is a normal phenomenon used to eliminate unnecessary or
incorrect cells. It is also used to remove cells which are injured
beyond repair. Thus apoptosis can be physiologic or pathologic
34. Differences between necrosis and apoptosis
Feature Necrosis Apoptosis
Control Uncontrolled pathological death of cells. Controlled death of cells. May be
physiologic or pathologic.
Cell size Enlarged. Reduced/shrinkage.
Cell lysis Yes. No. fragmentation into apoptic bodies.
Cellular content Enzymatic digestion. Leakage Intact. Present in apoptic bodies.
Nucleus Fragmentation into nucleosome-sized
fragments.
Enzyme participation Phospholipase and proteases are
important.
Caspases are activated.
Inflammation Frequent. Completely absent.
Phagocytic clearance Usually no. Yes.
Karyolysis
is
Karryorhex
Pyknosis
35. Pathologic calcification
• Definition:
Pathologic calcification is the abnormal (macroscopic) deposition
of calcium salts along iron, magnesium and other mineral salts in
the tissue.
• The calcium salts are deposited as fine, gritty, white granules or
clumps. The main deposit is crystalline calcium phosphate in the
form of an apatite similar to hydroxyapatite of bone.
• This deposition may be intracellular, extracellular or both.
36. Types
Dystrophic calcification Metastatic calcification
Occurs locally in dying tissues. Occurs in normal tissues.
May occur at normal serum level of Ca. Results from hypercalcemia or problems of calcium
metabolism.
